FCGR2A functional genetic variant associated with susceptibility to severe malarial anaemia in Ghanaian children.
Severe malarial anaemia is a major cause of mortality from malaria. Although of enormous relevance, its pathogenesis is largely unknown. Interestingly, the extent of anaemia greatly exceeds the loss of erythrocytes due to direct destruction by the pathogen Plasmodium falciparum. Immune response against the parasite is partially mediated through the Fc receptor for immunoglobulin (Ig) G IIa (FcgammaRIIa, CD32). The presence of an arginine instead of a histidine residue at amino acid position 131 (H131R) in the extracellular domain of FcgammaRIIa reduces the affinity of the receptor for IgG(2) and IgG(3) isotypes but increases the binding activity for C reactive protein (CRP). In Ghana, West Africa, 2504 children with severe malaria and 2027 matched healthy controls were studied for the FcgammaRIIa(H131R) polymorphism in order to ascertain its influence on major manifestations of the disease. The study group included patients with partly overlapping symptoms of severe malaria, among them 1591 cases with severe anaemia, 562 cases with cerebral malaria, and 497 cases with other malaria complications. Analyses of the genotype distributions indicated that, under a recessive model, FcgammaRIIa(131RR) was positively associated with severe malaria collectively (OR 1.20, 95% CI 1.05 to 1.38; p=0.007, p(corrected)=0.021) and, after stratification for phenotypes, with severe anaemia (OR 1.33, 95% CI 1.13 to 1.57; p=0.001, p(corrected)=0.009), but not with cerebral malaria (OR 1.04, 95% CI 0.82 to 1.33; p=0.733) or other malaria complications (OR 1.03, 95% CI 0.78 to 1.37; p=0.827). No association was found with levels of parasitaemia. The positive association with a CRP binding variant of FcgammaRIIa supports evidence for a role of CRP mediated defence mechanisms in the pathogenesis of severe malarial anaemia.


Three choices for death.
Ethicists and lobbyists for euthanasia have added qualifiers like "direct" and "indirect" to the word. Nonetheless, they still mean killing. E. Catherine Moroney, SSA, is a doctor of public health and a trustee of Greater Victoria Hospital Society in Victoria, British Columbia, and chairperson of its Patient Health Care Committee.


Thickening of a smectic membrane in an evanescent X-ray beam.
We report an unusual thickening of smectic membranes under the influence of X-ray irradiation below the critical angle. In the case of a four-layer film the thickness was found to grow at the footprint of the beam, reaching within minutes tens of layers. The effect is attributed to the localized energy dissipation of the evanescent wave. The "island" thus created is not connected to the meniscus and after the beam is switched off the film returns to its original state. A possible explanation is given in terms of a local disrupture of the tension of the smectic membrane.


[The effectiveness of anagrelide treatment in patients with Ph negative myeloproliferative diseases: influence on the incidence of thrombosis in the data from the Registry of patients with essential thrombocythemia and thrombocythemia associated with other myeloproliferative diseases treated with Thromboreductin® to the end of 2012].
In the Czech Republic, anagrelide (Thromboreductin®) [29] is used according to the recommendations of the Czech Working Group on Myeloproliferative Disorders (CZEMP) for treatment of thrombocythemia associated with Ph negative myeloproliferative disorders (MPDs). The patient data are collected in the Registry of patients with essential thrombocythemia (ET) and thrombocythemia associated with other MPDs treated with Thromboreductin®. At the end of 2012, the Registry contained data on 1,161 patients. Out of these, 1,159 patients with the dia-gnosis of a Ph negative MPD were evaluated. In 844 patients, precise WHO based dia-gnosis was known at start of therapy: 442 (52.4%) had ET, 108 (12.8%) had polycythaemia vera (PV) and 243 had primary myelofibrosis (PMF). The median age was 51 years at the time of diagnosis. At the time of the evaluation of the population, the median was 59 years. Every year, the proportion of patients newly treated with anagrelide as a firstline treatment in accordance with the CZEMP guidelines has been increasing. A growing proportion of patients has been treated with an additional cytoreducing drug, such as hydroxyurea and interferon. The majority of the patients received also an antiaggregant (or anticoagulant). More than a half of patients harbors the JAK2 mutation. A prompt decrease of platelet counts (as the response to Thromboreductin® treatment) was documented in most of the patients. After one year, 86.9% of patients had a full or partial response. In poorer responders, combination cytoreductive treatment was administered rather then the escalation of the Thromboreductin® dosage. There were 461 thrombotic manifestations in 363 patients and 61 haemorrhagic events in 57 patients recorded in the patients history. In the course of treatment (followup; F U), thrombosis was diagnosed only 179-times in 136 patients. There were more haemorrhagic events during F U: 109 events in 83 patients. Upon comparison of the number of events during F U to their numbers in history, we found a twofold decrease in arterial thrombosis, an almost twofold decrease in microvascular thrombosis and even a 6.6- fold decrease in venous thromboembolism events. Bleeding episodes increased 1.8-fold during F U. However, the vast majority of these hemorrhagic events were clinically insignificant. In conclusion, the treatment strategy according to the CZEMP guidelines incorporating anagrelide is highly effective in reducing the platelet counts, strongly prevents venous events, reduces arterial events, and leads to an increase of minor hemorrhages.


Dynamic kinetic resolution of alpha-hydroxy acid esters
[formula: see text] Enzymatic resolution in combination with ruthenium-catalyzed racemization of the substrate led to dynamic kinetic resolution of alpha-hydroxy esters in good yields and excellent ee's. Studies of different parameters showed that the best results were obtained using Pseudomonas cepacia lipase, ruthenium catalyst 3, and 4-chlorophenyl acetate as acyl donor in cyclohexane.


Human lymphoblastoid cells with acquired resistance to C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid: a novel folate-based thymidylate synthase inhibitor.
We describe the characterization of human lymphoblastoid cell lines with acquired resistance (greater than 20,000-fold) to a novel folate-based thymidylate synthase (TS) (EC 126.96.36.199) inhibitor, C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI198583). This acquired resistance was associated with a 64-fold amplification of the TS gene, a similar elevation in the corresponding mRNA, and an approximately 200-fold increase in both TS activity and TS protein. This amplification was maintained when the cells were grown in the absence of the selective agent, ICI198583, for 340 generations. TS isolated from one of the resistant cell lines, W1-L2:C1, displayed inhibition kinetic parameters similar to those of TS isolated from the parent W1-L2 cell line. It thus appears unlikely that resistance is due to an altered TS enzyme having a lower affinity for ICI198583. The resistant cell line, W1-L2:C1, was cross-resistant to other folate-based TS inhibitors but was as sensitive as the parent cell line, W1-L2, to 5-fluorodeoxyuridine. The W1-L2:C1 cell line was collaterally sensitive to the classical dihydrofolate reductase (EC 18.104.22.168) inhibitor methotrexate as well as to the lipophilic dihydrofolate reductase inhibitors metoprine and 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazolin e glucuronic acid salt (also called trimetrexate). When the W1-L2 and W1-L2:C1 cell lines were exposed to 1 microM ICI198583 for 24 h they accumulated the same concentration of total cellular ICI198583 polyglutamates despite the fact that the latter cell line accumulated a 300-fold greater concentration of ICI198583 monoglutamate. As polyglutamates, the tetra- and pentaglutamate forms predominated in the W1-L2 cell line, whereas the diglutamate form predominated in the W1-L2:C1 cell line, with few higher polyglutamates being detected. The lack of tri- and higher polyglutamates of ICI198583 (i.e., the more active species) in the W1-L2:C1 cell line may also contribute to the observed resistance. These findings may have important implications in light of the rapid onset of resistance to antifolates in the clinic.


Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.
Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.


Vancomycin pharmacokinetics and pharmacodynamics during short daily hemodialysis.
Short daily hemodialysis (SDHD) is an alternative to thrice-weekly HD because of its putative physiologic benefits. The purpose of this study was to investigate the effect of SDHD on the pharmacokinetics and pharmacodynamics of vancomycin. Six noninfected adults who had anuria and were treated with SDHD were studied and received four dialysis sessions over 4 days. After completion of the first SDHD, each patient received vancomycin 15 mg/kg by intravenous infusion. Blood samples were collected over the ensuing 3 days during each subsequent inter- and intradialytic period. Pharmacokinetic parameters were determined. Serum concentration-time profiles were simulated for four vancomycin regimens with maintenance doses administered after every other SDHD. Area under the serum-concentration time curve (AUC) from 0 to 48 hours, 48 to 96 hours, and 96 to 144 hours were calculated, and Monte Carlo simulations were performed to determine the probability of target attainment at an AUC/minimum inhibitory concentration (MIC) ratio ≥800 for each 48-hour AUC at MICs ranging from 0.5 to 2.0 μg/ml. Median (range) systemic clearance was 7.2 ml/min (5.3 to 10.0 ml/min), and dialytic clearance was 104 ml/min (94 to 106 ml/min). The steady-state volume of distribution was 55.4 L (34.8 to 77.2 L). At MICs ≤1 μg/ml, probability of target attainment was >90% for each 48-hour AUC when vancomycin was administered as a 20-mg/kg loading dose followed by 10 mg/kg after every other SDHD. Vancomycin pharmacokinetic parameters in SDHD are consistent with data from thrice-weekly HD. A loading dose of 20 mg/kg followed by 10 mg/kg after every other SDHD provides adequate exposure for pathogens with MICs ≤1 μg/ml.


Secondary Focal Segmental Glomerulosclerosis: From Podocyte Injury to Glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is a common cause of proteinuria and nephrotic syndrome leading to end stage renal disease (ESRD). There are two types of FSGS, primary (idiopathic) and secondary forms. Secondary FSGS shows less severe clinical features compared to those of the primary one. However, secondary FSGS has an important clinical significance because a variety of renal diseases progress to ESRD thorough the form of secondary FSGS. The defining feature of FSGS is proteinuria. The key event of FSGS is podocyte injury which is caused by multiple factors. Unanswered questions about how these factors act on podocytes to cause secondary FSGS are various and ill-defined. In this review, we provide brief overview and new insights into FSGS, podocyte injury, and their potential linkage suggesting clues to answer for treatment of the disease.


Toxic effects of cadmium on flatworm stem cell dynamics: A transcriptomic and ultrastructural elucidation of underlying mechanisms.
Stem cells or undifferentiated cells can cope more easily with external stresses. To evaluate the impact of toxic compounds on stem cell dynamics in vivo, in relation to other biological responses, we use the carcinogenic element cadmium and the regenerating model organism Macrostomum lignano. Through both BrdU and anti-histone H3 immunostainings, cadmium-induced effects were investigated at different stages of the stem cell cycle. A 24-h exposure to 100 and 250 μM CdCl2 significantly decreased the number of stem cells (neoblasts) in mitosis, whereas the number of cells in the S phase remained unchanged. After this short-term exposure, the ultrastructure of the neoblasts was minimally affected in contrast to the epidermal tissues. These results were supported by gene expression data: transcripts of cdc2 and pig3 were significantly upregulated during all treatments. Both genes are involved in the cell cycle progression and are transcribed in the gonadal region, where stem cells are highly represented. Based on a substantial increase in gene expression of heat shock proteins (HSP) and their high activity in the gonadal region, we hypothesize that these proteins are key players in the protection of stem cells against external stresses. Apart from the strong HSP induction, other protective processes including cell division, apoptosis and anti-oxidative defence, were also activated. We, therefore, conclude that the protection of stem cells against external stressors may be based on the interplay between stem cell maintenance, i.e. repair and recovery through division, on one hand and apoptosis on the other hand. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1217-1228, 2016.


Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures.
Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signaling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described. Here we characterize the interactions of two such mutants, Mps1 C604Y and C604W, which raise resistance to two closely related compounds, NMS-P715 and its derivative Cpd-5, but not to the well characterized Mps1 inhibitor, reversine. We show that estimates of the IC50 (employing a novel specific and efficient assay that utilizes a fluorescently labeled substrate) and the binding affinity (KD ) indicate that, in both mutants, Cpd-5 should be better tolerated than the closely related NMS-P715. To gain further insight, we determined the crystal structure of the Mps1 kinase mutants bound to Cpd-5 and NMS-P715 and compared the binding modes of Cpd-5, NMS-P715, and reversine. The difference in steric hindrance between Tyr/Trp604 and the trifluoromethoxy moiety of NMS-P715, the methoxy moiety of Cpd-5, and complete absence of such a group in reversine, account for differences we observe in vitro Our analysis enforces the notion that inhibitors targeting Mps1 drug-resistant mutations can emerge as a feasible intervention strategy based on existing scaffolds, if the clinical need arises.


Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis.
Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification. A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients. Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations. The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.


Extracellular nucleotide receptor inhibits AVP-stimulated water permeability in inner medullary collecting duct.
The P2u class of nucleotide receptors is linked to mobilization of intracellular Ca2+ in many cell types, including the renal collecting duct cells. In the present studies, we examined the effects of nucleotides (ATP, UTP, and ADP; 10 microM each) on the arginine vasopressin (AVP, 0.1 nM)-stimulated osmotic water permeability (Pf) in in vitro perfused terminal inner medullary collecting ducts (IMCD) of rat. ATP or UTP, when added to the bath, decreased the AVP-stimulated Pf by approximately 40%. These effects were reversible upon withdrawal of the nucleotides. However, addition of ADP to the bath or sham exchange of the bath had no significant effect on the Pf. Furthermore, ATP did not have any significant effect on the Pf stimulated either by a membrane-permeant, nonhydrolyzable adenosine 3',5'-cyclic monophosphate (cAMP) analogue [8-(4-chlorophenylthio)-cAMP, 0.1 mM] o by forskolin (1 microM). In line with these findings, ATP decreased the AVP-stimulated cAMP levels in IMCD suspensions to approximately 68%. In addition, ATP did not exert an inhibitory effect on the AVP-stimulated Pf in the presence of calphostin C (150 nM), an inhibitor of protein kinase C. These results lead us to conclude the following: 1) agonist occupancy of the putative nucleotide receptor in the terminal IMCD causes an inhibition of AVP-stimulated Pf; and 2) this effect is due to a decrease in cellular cAMP levels, most likely resulting from activation of the phosphoinositide signaling pathway.


Mental disorders and request for psychiatric intervention in an Italian local jail.
The issue of the prevalence of psychiatric illnesses in Italian prison samples has not received the same attention paid at an international level. The aims of the present study were to evaluate the prevalence of psychiatric disorders diagnosed according to DSM-III-R criteria among an Italian prisoner population, and to examine prisoners' requests for psychiatric intervention in relationship to the presence or absence of different psychiatric disorders. One hundred forty-two Italian male subjects from the Casa Circondariale of Messina, Italy, were evaluated using the Structured Clinical Interview for DSM-III-R Non-Patient Version - SCID I and SCID II. A very high rate of disorders was found among inmates: 85.2% (n=121) of the sample were affected by a psychiatric disorder. Of the total sample, 51.4% (n=73) had requested psychiatric treatment during detention. The detection, diagnosis and treatment of the mentally ill prisoners is a primary goal for a better organization of services and prison settings; screening procedures for evaluating the presence of psychiatric disorders, with the aim to promote differential strategies for the care and rehabilitation of inmates, are needed.


From guidelines to careflows: modelling and supporting complex clinical processes.
Research on computer interpretable clinical guidelines has largely focused on individual points of care rather than processes of care. Whether we consider simple aids like clinical alerts and reminders or more sophisticated data interpretation and decision-making, guideline developers tend to focus on specific tasks rather than processes like care plans and pathways which are extended in time. In contrast, research on business process modelling has demonstrated notations and tools which deal directly with process modelling, but has not been concerned with problems like data interpretation and decision making. In this chapter we describe these two traditions, and compare some of their strengths and weaknesses. We also briefly discuss the distinct theoretical frameworks which have grown up around them, notably Petri nets for workflow modelling and mathematical logics for guidelines. We conclude that these offer complementary views of clinical processes and that a key research challenge is find a way of unifying them.


[Correlation between cancer mortality and alcohol-related mortality in a South-Hungarian village].
The author, who had former practical experience in the research-field of the medical statistics and alcohol-epidemiology, has collected the data of the total, and the cause-specific mortality continuously in the village where he has worked as the single GP from December 1986 to 1999. The village is located in the Great Hungarian Plain. It is an agricultural community, currently with population of 2042 inhabitants. The longevity in the village was above the national average. Total mortality and cause specific mortality in the village were calculated between January 1, 1987 and December 31, 1999. During the period, 503 people died. From these 278 (55.3%) were male, and 225 (44.7%) were female. 118 deaths, 23.5% of all deaths in the village were cancer-related. 67.7% (80 cases) of these were among males, and 32.3% (38 cases) among females. 40.7% (48 cases) of cancer-related deaths were attributable to gastrointestinal-tract cancers (ICD 10 C15-C26). The proportion of deaths which were directly or indirectly alcohol-related was 35.8% (180 cases) of the total mortality. In 50% (90 causes) of these deaths, the cause of death was one of the "especially characteristic death's cause of alcoholics". Proportion of alcohol-related-mortality attributable to cancer-related causes was high as 23.9% (43 cases); and vice versa: proportion of cancer-mortality attributable to alcohol-related causes was 36.4% (50% among males, and only 7.9% among females). Cancers of the cavity of mouth and pharynx as cause of death (6 cases) occurred only among alcohol-addicted males. The most important epidemiological conclusion is that the prevention of alcoholism/alcohol abuse is one of the most promising way for the prevention of (certain) cancers, too.


[Marie Rennotte, educator and medical doctor: elements for a historical and biographical, social and medical study].
At the time of Marie Rennotte's 150th birthday celebrations, a new focus on her meaningful actions as a Belgian-Brazilian pioneer professional in Education and Science in São Paulo at the turn of the 19th to the 20th centuries begins to take place. The present paper is a preliminary chronological draft with bibliography and recommended documents that will allow researchers from different areas to develop deeper historic, biographical, medical and social studies demanded by Rennotte's extraordinary personal dimensions and the unusual scope of her actions in São Paulo society.


Comparative efficacy of chloramphenicol loaded chondroitin sulfate and dextran sulfate nanoparticles to treat intracellular Salmonella infections.
Salmonella Paratyphi A is a food-borne Gram-negative pathogen and a major public health challenge in the developing world. Upon reaching the intestine, S. Paratyphi A penetrates the intestinal epithelial barrier; and infects phagocytes such as macrophages and dendritic cells. S. Paratyphi A surviving within macrophages is protected from the lethal action of antibiotics due to their poor penetration into the intracellular compartments. Hence we have developed chloramphenicol loaded chondroitin sulfate (CS-Cm Nps) and dextran sulfate (DS-Cm Nps) nanoparticles through ionotropic-gelation method for the intracellular delivery of chloramphenicol. The size of these nanoparticles ranged between 100 and 200 nm in diameter. The encapsulation efficiency of both the nanoparticles was found to be around 65%. Both the nanoparticles are found to be non-hemolytic and non-toxic to fibroblast and epithelial cells. The prepared nanoparticles exhibited sustained release of the drug of up to 40% at pH 5 and 20-25% at pH 7.0 after 168 h. The anti-microbial activities of both nanoparticles were tested under in vitro and ex vivo conditions. The delivery of DS-Cm Nps into the intracellular compartments of the macrophages was 4 fold more compared to the CS-Cm Nps which lead to the enhanced intracellular antimicrobial activity of Ds-Cm Nps. Enhanced anti-microbial activity of Ds-Cm Nps was further confirmed in an ex vivo chicken intestine infection model. Our results showed that Cm loaded DS Nps can be used to treat intracellular Salmonella infections.


Tobacco dependence treatments: review and prospectus.
Cigarette smoking continues to place an enormous burden on US health systems. The treatment of tobacco-dependent persons is vital to the public health, since unmitigated smoking could lead to the development of disease and premature death in as many as 20 million current smokers in the United States. Much of this tobacco-related morbidity and mortality could be prevented by the application of existing treatments, as well as newer ones. Access to safe and effective treatments was significantly expanded in 1996, when two forms of nicotine replacement therapy (NRT), the nicotine gum and patch, became available for over-the-counter sale. Expanded access has led to significantly increased utilization and quitting. Even with these advances, however, the scope of this tobacco dependence demands that we explore alternative treatment strategies, including exposure reduction therapy (ERT) as a possible option for smokers not currently making quit attempts. In this review, we present principles to guide the development of such a therapy, and for its application, should it be proven effective.


Assessment of serum prolactin levels in patients with systemic lupus erythematosus.
To determine the relationship between hyperprolactinemia levels and clinical features of patients with systemic lupus erythematosus (SLE), a descriptive, correlational and cross-sectional study, was performed in female patients over 18 years old, who attended the Rheumatology Clinic at the Hospital Universitario, in Maracaibo, Venezuela, from November 2012 to June 2013. They underwent a comprehensive medical history evaluation, based on interviews and physical examination, with emphasis on the search for clinical manifestations of lupus activity. Blood samples were taken in order to determine prolactin levels at the moment of the patient evaluation. Values from 2.1 to 47.6 ng/mL were considered as normal. The population was classified into two groups: a group formed by 28 women with lupus crisis and another group formed by 22 patients without crisis. The average prolactin serum level was 39.0 ± 59.5 ng/dL for the first group and 14.2 ± 7.2 ng/dL for the second group, indicating statistical significance (p = 0.044). Patients with lupus crisis had prolactin values higher than those of asymptomatic patients, although only one-seventh of them had absolute hyperprolactinemia. All asymptomatic patients had normal levels of prolactin. All patients with hyperprolactinemia were in lupus crisis.


Sentence level auditory comprehension treatment program for aphasic adults.
The purpose of this study was to investigate whether a newly developed sentence level auditory comprehension (SLAC) treatment program could be used to improve language comprehension test scores in adults with chronic aphasia. Results indicate that the SLAC treatment program can be used with chronic patients; performance on a standardized test (the Token Test) was improved after treatment; and improved performance could not be predicted from either anatomic CT scan lesion sites or pretreatment test scores. One advantage to the SLAC treatment program is that the patient can practice listening independently with a tape recorder device (Language Master) and earphones either in the hospital or at home.


Internet-initiated sex crimes against minors: implications for prevention based on findings from a national study.
To describe the characteristics of episodes in which juveniles became victims of sex crimes committed by people they met through the Internet. A national survey of a stratified random sample of 2574 law enforcement agencies conducted between October 2001 and July 2002. Telephone interviews were conducted with local, state, and federal law enforcement investigators concerning 129 sexual offenses against juvenile victims that originated with online encounters. Victims in these crimes were primarily 13- through 15-year-old teenage girls (75%) who met adult offenders (76% older than 25) in Internet chat rooms. Most offenders did not deceive victims about the fact that they were adults who were interested in sexual relationships. Most victims met and had sex with the adults on more than one occasion. Half of the victims were described as being in love with or feeling close bonds with the offenders. Almost all cases with male victims involved male offenders. Offenders used violence in 5% of the episodes. Health care professionals and educators, parents and media need to be aware of the existence, nature and real life dynamics of these online relationships among adolescents. Information about Internet safety should include frank discussion about why these relationships are inappropriate, criminal, and detrimental to the developmental needs of youth.


[Is DSM IV of value in training of psychiatrists?].
Acquiring the skill to be a psychiatrist requires learning in three fields: academic, clinical and research. Academic training includes various kinds of objectives which are analysed and to which the DSM IV provides only an imperfect response. Clinical training which shapes clinical practice, requires the organization of knowledge: the DSM IV, in so far as it analyses and classifies data is a useful tool, but the utility is limited since the DSM IV is inherently biased towards a psychiatric view of illness. The utility of the DSM IV is analysed for research training, particularly with the triple goal of preparing for the manipulation of knowledge, for practical care, and for the transmission of knowledge.


Influence of application amount on sunscreen photodegradation in in vitro sun protection factor evaluation: proposal of a skin-mimicking substrate.
Widely used polymethylmethacrylate substrates for in vitro sun protection factor (SPF) testing of sunscreens do not mimic the rough surface structure of skin, and in addition, sample loading is less than that used in in vivo SPF testing (2.00 mg cm(-2)). We have developed a skin-mimicking substrate (SMS), which has furrows and ridges on its surface, like human skin. A comparison of the photodegradation profiles of sunscreens on commercially available substrates (including SMS) at the recommended application amounts, and on SMS at various application amounts showed that the photodegradation rate of photounstable sunscreen was dependent on the application amount being higher at lower application amounts. SMS at the recommended application amount of 2.00 mg cm(-2) provided in vitro SPF values that were comparable with in vivo SPF values. Our results confirm that, in order to develop a reliable in vitro SPF method, which is consistent with in vivo SPF determination, it is important to use the same application amount of sample as in the in vivo method, in order to take proper account of sunscreen photostability.


The context-specific proportion congruent Stroop effect: location as a contextual cue.
The Stroop effect has been shown to depend on the relative proportion of congruent and incongruent trials. This effect is commonly attributed to experiment-wide word-reading strategies that change as a function of proportion congruent. Recently, Jacoby, Lindsay, and Hessels (2003) reported an item-specific proportion congruent effect that cannot be due to these strategies and instead may reflect rapid, stimulus driven control over word-reading processes. However, an item-specific proportion congruent effect may also reflect learned associations between color word identities and responses. In two experiments, we demonstrate a context-specific proportion congruent effect that cannot be explained by such word-response associations. Our results suggest that processes other than learning of word-response associations can produce contextual control over Stroop interference.


Casting light on xylem vulnerability in an herbaceous species reveals a lack of segmentation.
Finding thresholds at which loss of plant functionality occurs during drought is critical for predicting future crop productivity and survival. Xylem resistance to embolism has been suggested as a key trait associated with water-stress tolerance. Although a substantial literature exists describing the vulnerability of woody stems to embolism, leaves and roots of herbaceous species remain under-represented. Also, little is known about vulnerability to embolism at a whole-plant scale or propagation of embolism within plants. New techniques to view the process of embolism formation provide opportunities to resolve long-standing questions. Here, we used multiple visual techniques, including X-ray micro-computed tomography and the optical vulnerability method, to investigate the spread of embolism within intact stems, leaves and roots of Solanum lycopersicum (common tomato). We found that roots, stems and leaves of tomato plants all exhibited similar vulnerability to embolism, suggesting that embolism rapidly propagates among tissues. Although we found scarce evidence for differentiation of xylem vulnerability among tissues at the scale of the whole plant, within a leaf the midrib embolized at higher water potentials than lower order veins. Substantial overlap between the onset of cavitation and incipient leaf damage suggests that cavitation represents a substantial damage to plants, but the point of lethal cavitation in this herbaceous species remains uncertain.


Characterization of protein complexes and subcomplexes in protein-protein interaction databases.
The identification and characterization of protein complexes implicated in protein-protein interaction data are crucial to the understanding of the molecular events under normal and abnormal physiological conditions. This paper provides a novel characterization of subcomplexes in protein interaction databases, stressing definition and representation issues, quantification, biological validation, network metrics, motifs, modularity, and gene ontology (GO) terms. The paper introduces the concept of "nested group" as a way to represent subcomplexes and estimates that around 15% of those nested group with the higher Jaccard index may be a result of data artifacts in protein interaction databases, while a number of them can be found in biologically important modular structures or dynamic structures. We also found that network centralities, enrichment in essential proteins, GO terms related to regulation, imperfect 5-clique motifs, and higher GO homogeneity can be used to identify proteins in nested complexes.


pyBrick-DNA: A Python-Based Environment for Automated Genetic Component Assembly.
Genetic component assembly is key in the simulation and implementation of genetic circuits. Automating this process, thus accelerating prototyping, is a necessity. We present pyBrick-DNA, a software written in Python, that assembles components for the construction of genetic circuits. pyBrick-DNA (colab.pyBrick.com) is a user-friendly environment where scientists can select genetic sequences or input custom sequences to build genetic assemblies. All components are modularly fused to generate a ready-to-go single DNA fragment. It includes Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and plant gene-editing components. Hence, pyBrick-DNA can generate a functional CRISPR construct composed of a single-guided RNA integrated with Cas9, promoters, and terminator elements. The outcome is a DNA sequence, along with a graphical representation, composed of user-selected genetic parts, ready to be synthesized and cloned in vivo. Moreover, the sequence can be exported as a GenBank file allowing its use with other synthetic biology tools.


Correlation of hair mineral concentrations with insulin resistance in Korean males.
Calcium and magnesium that are associated with insulin resistance play an antagonistic role with each other in cells. This study was conducted to investigate the relationship between hair mineral concentrations and insulin resistance in Korean adult males. A total of 123 male subjects (63 patients with metabolic syndrome and 60 normal control patients) were recruited and fasting plasma glucose, total cholesterol, triglyceride, as well as HDL cholesterol levels, HOMA-IR, and hair mineral concentrations were measured. The ratio of calcium/magnesium in hair showed a significantly positive correlation with the HOMA-IR (r = 0.191, P = 0.038) and insulin (r = 0.198, P = 0.031). The result of multiple regression analysis after adjusting the age also showed a significant correlation of the Ca/Mg ratio with HOMA-IR (R² = 0.115, P = 0.047). The hair chromium concentration was lower in the metabolic syndrome group than in the control group, and it showed a significantly negative correlation with the fasting blood glucoseand the triglyceride. The result of this study showed that insulin resistance increased as the ratio of Ca/Mg increased, or as the chromium concentration in hair decreased.


[Phospholipid content of plasma membranes and phospholipase C activity in epithelial cells of the large intestine in colitis-associated carcinogenesis in rats].
The decrease of major cytoplasmic membrane phospholipids (phosphatidylcholine and phosphatidylethanolamine) content was established in mucosal epithelial cell under colon inflammation pathology--ulcerative colitis. It was shown that aforementioned changes were associated with the increase of phospholipids' hydrolyzing enzyme--phospholipase C activity and intracellular Ca2+ concentration enlargement. Carcinogenesis stimulation under inflammation was accompanied by phospholipase C activity increase when quantity of investigated phospholipids (phosphatidylcholine, phosphatidylinozytol, phosphatidylserine) separately decreased and cytoplasmic Ca2+ value normalization was established.


Risk factors and primary prevention trials for type 1 diabetes.
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease resulting in the designated immune destruction of insulin producing β-cells, usually diagnosed in youth, and associated with important psychological, familial, and social disorders. Once diagnosed, patients need lifelong insulin treatment and will experience multiple disease-associated complications. There is no cure for T1DM currently. The last decade has witnessed great progress in elucidating the causes and treatment of the disease based on numerous researches both in rodent models of spontaneous diabetes and in humans. This article summarises our current understanding of the pathogenesis of T1DM, the roles of the immune system, genes, environment and other factors in the continuing and rapid increase in T1DM incidence at younger ages in humans. In addition, we discuss the strategies for primary and secondary prevention trials of T1DM. The purpose of this review is to provide an overview of this disorder's pathogenesis, risk factors that cause the disease, as well as to bring forward an ideal approach to prevent and cure the disorder.


Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration.
Axon regeneration is arrested in the injured central nervous system (CNS) by axon growth-inhibitory ligands expressed in oligodendrocytes/myelin, NG2-glia, and reactive astrocytes in the lesion and degenerating tracts, and by fibroblasts in scar tissue. Growth cone receptors (Rc) bind inhibitory ligands, activating a Rho-family GTPase intracellular signaling pathway that disrupts the actin cytoskeleton inducing growth cone collapse/repulsion. The known inhibitory ligands include the chondroitin sulfate proteoglycans (CSPG) Neurocan, Brevican, Phosphacan, Tenascin, and NG2, as either membrane-bound or secreted molecules; Ephrins expressed on astrocyte/fibroblast membranes; the myelin/oligodendrocyte-derived growth inhibitors Nogo, MAG, and OMgp; and membrane-bound semaphorins (Sema) produced by meningeal fibroblasts invading the scar. No definitive CSPG Rc have been identified, although intracellular signaling through the Rho family of G-proteins is probably common to all the inhibitory ligands. Ephrins bind to signalling Ephs. The ligand-binding Rc for all the myelin inhibitors is NgR and requires p75(NTR) for transmembrane signaling. The neuropilin (NP)/plexin (Plex) Rc complex binds Sema. Strategies for promoting axon growth after CNS injury are thwarted by the plethora of inhibitory ligands and the ligand promiscuity of some of their Rc. There is also paradoxical reciprocal expression of many of the inhibitory ligands/Rc in normal and damaged neurons, and NgR expression is restricted to a limited number of neuronal populations. All these factors, together with an incomplete understanding of the normal functions of many of these molecules in the intact CNS, presently confound interpretive acumen in regenerative studies.


The evolutionary dynamics of direct phenotypic overdominance: emergence possible, loss probable.
An evolutionary dynamical system with explicit diploid genetics is used to investigate the likelihood of observing phenotypically overdominant heterozygotes versus heterozygous phenotypes that are intermediate between the homozygotes. In this model, body size evolves in a population with discrete demographic episodes and with competition limiting reproduction. A genotype-phenotype map for body size is used that can generate the two qualitative types of dominance interactions (overdominance versus intermediate dominance). It is written as a single-locus model with one focal locus and parameters summarizing the effects of alleles at other loci. Two types of evolutionarily stable strategy (ESS; continuously stable strategy, CSS) occur. The ESS is generated either (1) by the population ecology; or (2) by a local maximum of the genotype-phenotype map. Overdominant heterozygotes are expected to arise if the population evolves toward the second type of ESS, where nearly maximum body sizes are found. When other loci with partially dominant inheritance also evolve, the location of the maximum in the genotype-phenotype map repeatedly changes. It is unlikely that an evolving population will track these changes; ESSs of the second type now are at best quasi-stationary states of the evolutionary dynamics. Considering the restrictions on its probability, a pattern of phenotypic overdominance is expected to be rare.


Differential Early Secreted Antigen Target (ESAT) 6 kDa-induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis.
Expression of Suppressor of cytokine signaling (SOCS)-1 molecules is increased in patients with tuberculosis (TB). Early Secreted Antigen Target (ESAT)-6 kDa - induced IFN-γ responses indicate Mycobacterium tuberculosis infection. The effect of ESAT6- stimulation on SOCS1 in the host is not known. Healthy asymptomatic controls had a negative (n = 16) or a positive ( n = 13) tuberculin skin test (TST). ESAT6-induced IFN-γ responses classified these controls as positive (EC ESAT6 IFN-γ (+), n = 5) or negative (EC ESAT6 IFN-γ (-), n = 24) responders. Patients had pulmonary (n = 21) or extra-pulmonary (n = 30) tuberculosis. Peripheral blood cells were stimulated with ESAT6 and mRNA expression of IFN-γ and SOCS1 was determined. ESAT6-induced IFN-γ expression was raised in EC ESAT6 IFN-γ (+) as compared with EC ESAT6 IFN-γ (-), p = 0.019. ESAT6-induced SOCS1 mRNA expression was increased in both pulmonary TB and extra-pulmonary TB patients as compared with both EC groups. ESAT6-induced IFN-γ/SOCS1 mRNA expression ratio was decreased in TB patients as compared with both EC groups. M. tuberculosis infection induces increased ESAT6-induced IFN-γ responses in both latent and active TB. Our data shows down-regulation of IFN-γ / SOCS1 expression to be induced only in active TB cases, distinguishing them from healthy individuals likely to have latent TB. A decreasing IFN-γ /SOCS1 ratio may leads to reduced Th1 immunity which contributes to inability of the host to control clinical disease.


Flap classification and survival factors. Current concepts.
Flap survival variables are different for each type of flap and for each anatomic location. One must have sound knowledge concerning tissue survivability for all types of flaps. Otherwise, a high rate of failure may be experienced. A thorough knowledge of blood flow patterns of the foot and leg is paramount, as well as insight to the basic fundamental concepts concerning flap mechanics. These fundamentals include delay phenomenon, designing flaps, length-to-width ratios, and evaluation of flap vascularity. Successful and appropriate use of flaps in the lower extremity can be rewarding and provide the surgeon with a powerful tool to use in reconstructive procedures. Inappropriate or poorly performed flap procedures often create situations that are more difficult to manage than the original problem. According to Hoopes, "flaps are vicarious, mischievous, and frequently insubordinate reconstructive agents. They demand thorough understanding and meticulous attention for successful employment." Therefore, judicial use of these procedures is recommended.


Progress in electrospun composite nanofibers: composition, performance and applications for tissue engineering.
The discovery of novel methods to fabricate optimal scaffolds that mimic both mechanical and functional properties of the extracellular matrix (ECM) has always been the "holy grail" in tissue engineering. In recent years, electrospinning has emerged as an attractive material fabrication method and has been widely applied in tissue engineering due to its capability of producing non-woven and nanoscale fibers. However, from the perspective of biomimicry, it is difficult for single-component electrospun fiber membranes to achieve the biomimetic purposes of the multi-component extracellular matrix. Based on electrospinning, various functional components can be efficiently and expediently introduced into the membranes, and through the complementation and correlation of the properties of each component, composite materials with comprehensive and superior properties are obtained while maintaining the primitive merits of each component. In this review, we will provide an overview of the attempts made to fabricate electrospinning-based composite tissue engineering materials in the past few decades, which have been divided into organic additives, inorganic additives and organic-inorganic additives.


Quantitative and qualitative characterization of aflatoxin B1 adducts formed in vivo within the ribosomal RNA genes of rat liver DNA.
We have examined the time course and patterns of covalent aflatoxin B1:DNA adducts produced within the ribosomal RNA gene sequences isolated from the liver nuclear DNA of aflatoxin B1-treated animals. Liver nuclear DNA was initially enriched in ribosomal DNA by cesium salt density centrifugation, and incubated under alkaline conditions to stabilize bound aflatoxin B1-DNA moieties. Alkali-treated DNA was hybridized to 18S and 28S rRNA, and the RNA:DNA hybrids were recovered by cesium chloride centrifugation. Ribosomal DNA sequences within nuclear DNA were found to be preferential targets for aflatoxin B1 modification. Over a 12-h period after administration of 1-mg [3H]aflatoxin B1/kg dose ribosomal DNA contained 4 to 5 times more aflatoxin B1 residues per mg DNA than did total nuclear DNA. Aflatoxin B1 residues bound to ribosomal DNA were also found to be removed more rapidly than from total nuclear DNA by a factor of 5.7 over the 12-h period postdosing. Levels of the principal aflatoxin B1 adduct, 2,3-dihydro-3-hydroxy(N7-guanyl)aflatoxin B1, as well as the stable formamidopyrimidine derivatives of the parent adduct were also determined. Nuclear DNA isolates were heated to induce depurination of the principal N7-guanine adduct, and differences in adduct levels between alkali-treated (stabilized) and depurinated DNA samples were taken as an approximation of initial levels of this aflatoxin B1:DNA moiety in ribosomal isolates. No differences in the proportions of these aflatoxin B1:DNA adduct species were found in ribosomal as compared to total nuclear DNA, and we conclude that the preferential formation and removal of aflatoxin B1:DNA moieties within ribosomal DNA is not associated with a pattern of adducts qualitatively different from that in total nuclear DNA.


DIALing-up the preclinical characterization of gene-modified adoptive cellular immunotherapies.
The preclinical characterization of gene modified adoptive cellular immunotherapy candidates for clinical development often requires the use of mouse models. Gene-modified lymphocytes (GML) incorporating chimeric antigen receptors (CAR) and T-cell receptors (TCR) into immune effector cells require in vivo characterization of biological activity, mechanism of action, and preclinical safety. Typically, this characterization involves the assessment of dose-dependent, on-target, on-tumor activity in severely immunocompromised mice. While suitable for the purpose of evaluating T cell-expressed transgene function in a living host, this approach falls short in translating cellular therapy efficacy, safety, and persistence from preclinical models to humans. To comprehensively characterize cell therapy products in mice, we have developed a framework called "DIAL". This framework aims to enable an end-to-end understanding of genetically engineered cellular immunotherapies in vivo, from infusion to tumor clearance and long-term immunosurveillance. The acronym DIAL stands for Distribution, Infiltration, Accumulation, and Longevity, compartmentalizing the systemic attributes of gene-modified cellular therapy and providing a platform for optimization with the ultimate goal of improving therapeutic efficacy. This review will discuss both existent and emerging examples of DIAL characterization in mouse models, as well as opportunities for future development and optimization.


Active transport of potassium by insect midgut.
Midguts isolated from fifth-instar larvae of the insert Hyalophora cecropia actively transport potassium in the hemolymph to lumen direction. No specific co- or counter-ion is required and other alkali ions are actively transported in the same direction as potassium. No specific inhibitor of K+ active transport has been found although most metabolic inhibitors reduce the net K+ flux, potential difference, and short-circuit current to zero. The site of the epithelial active transport of potassium has been identified by microelectrode measurements of intracellular resistance as the goblet cell, one of the two major cell types in the single-layered midgut. Under certain external conditions, the neighboring columnar cells are added to the goblet cell transport route through intercellular electrical coupling that occurs after application of external depolarizing current. Tracer influx kinetics were used to establish that the fraction of exchangeable K involved in the transport route under open-circuit conditions is small, corresponding to a goblet cell pathway. Under depolarizing current conditions, virtually all of the exchangeable midgut K is involved in the transport route, corresponding to a goblet and columnar cell pathway. These results and others are used to construct a model for rheogenic active transport of potassium in insect midgut.


Morphologic and cytochemical characteristics of blood cells and hematologic and plasma biochemical reference ranges in green iguanas.
To determine blood cell morphologic characteristics and hematologic and plasma biochemical reference ranges for iguanas housed in a warm indoor and outdoor environment with regular exposure to direct sunlight. Original study. 51 clinically normal iguanas (18 males, 25 females, and 8 juveniles) housed in 3 Florida locations. Blood was collected from the coccygeal or ventral abdominal vein. Any samples that had obvious hemolysis or clot formation were not used. Leukocyte counts were determined manually; other hematologic values were obtained by use of a commercially available cell counter. Plasma biochemical values were determined by use of a spectrophotometric chemistry analyzer. Blood smears were stained with Wright-Giemsa and cytochemical stains for morphologic and cytochemical evaluation. Hematologic ranges were generally higher in this study than previously reported. Thrombocytes were variable in appearance between individuals and sometimes difficult to distinguish from lymphocytes on a Wright-Giemsa preparation. Concentrations of calcium, phosphorus, total protein, globulins, and cholesterol were significantly higher, and the albumin:globulin ratio was significantly lower, in healthy gravid females than in male or nongravid female iguanas. Nongravid females had significantly higher calcium and cholesterol concentrations, compared with males. The calcium:phosphorus ratio was > 1 in all iguanas. Gravid females had a calcium phosphorus product ranging between 210 and 800. Intracytoplasmic inclusions were identified within the erythrocytes of some iguanas. Hematologic ranges for iguanas in this study are higher than those reported for iguanas. Sex and age of the iguana should be considered when evaluating biochemical values. Healthy ovulating and gravid females may have significantly increased electrolyte and protein concentrations, but maintain a calcium:phosphorus ratio > 1.


Preoperative and early postoperative seizures in patients with glioblastoma-two sides of the same coin?
Symptomatic epilepsy is a common symptom of glioblastoma, which may occur in different stages of disease. There are discrepant reports on association between early seizures and glioblastoma survival, even less is known about the background of these seizures. We aimed at analyzing the risk factors and clinical impact of perioperative seizures in glioblastoma. All consecutive cases with de-novo glioblastoma treated at our institution between 01/2006 and 12/2018 were eligible for this study. Perioperative seizures were stratified into seizures at onset (SAO) and early postoperative seizures (EPS, ≤21days after surgery). Associations between patients characteristics and overall survival (OS) with SAO and EPS were addressed. In the final cohort (n = 867), SAO and EPS occurred in 236 (27.2%) and 67 (7.7%) patients, respectively. SAO were independently predicted by younger age (P = .009), higher KPS score (P = .002), tumor location (parietal lobe, P = .001), GFAP expression (≥35%, P = .045), and serum chloride at admission (>102 mmol/L, P = .004). In turn, EPS were independently associated with tumor location (frontal or temporal lobe, P = .013) and pathologic laboratory values at admission (hemoglobin < 12 g/dL, [P = .044], CRP > 1.0 mg/dL [P = 0.036], and GGT > 55 U/L [P = 0.025]). Finally, SAO were associated with gross-total resection (P = .006) and longer OS (P = .030), whereas EPS were related to incomplete resection (P = .005) and poorer OS (P = .009). In glioblastoma patients, SAO and EPS seem to have quite different triggers and contrary impact on treatment success and OS. The clinical characteristics of SAO and EPS patients might contribute to the observed survival differences.


Accuracy of prehospital triage protocols in selecting severely injured patients: A systematic review.
Prehospital trauma triage ensures proper transport of patients at risk of severe injury to hospitals with an appropriate corresponding level of trauma care. Incorrect triage results in undertriage and overtriage. The American College of Surgeons Committee on Trauma recommends an undertriage rate below 5% and an overtriage rate below 50% for prehospital trauma triage protocols. To find the most accurate prehospital trauma triage protocol, a clear overview of all currently available protocols and corresponding outcomes is necessary. The aim of this systematic review was to evaluate the current literature on all available prehospital trauma triage protocols and determine accuracy of protocol-based triage quality in terms of sensitivity and specificity. A search of Pubmed, Embase, and Cochrane Library databases was performed to identify all studies describing prehospital trauma triage protocols before November 2016. The search terms included "trauma," "trauma center," or "trauma system" combined with "triage," "undertriage," or "overtriage." All studies describing protocol-based triage quality were reviewed. To assess the quality of these type of studies, a new critical appraisal tool was developed. In this review, 21 articles were included with numbers of patients ranging from 130 to over 1 million. Significant predictors for severe injury were: vital signs, suspicion of certain anatomic injuries, mechanism of injury, and age. Sensitivity ranged from 10% to 100%; specificity from 9% to 100%. Nearly all protocols had a low sensitivity, thereby failing to identify severely injured patients. Additionally, the critical appraisal showed poor quality of the majority of included studies. This systematic review shows that nearly all protocols are incapable of identifying severely injured patients. Future studies of high methodological quality should be performed to improve prehospital trauma triage protocols. Systematic review, level III.


Perturbations of aromatic amino acids are associated with iron cluster assembly in ribonucleotide reductase.
The β2 subunit of class Ia ribonucleotide reductases (RNR) contains an antiferromagnetically coupled μ-oxo bridged diiron cluster and a tyrosyl radical (Y122•). In this study, an ultraviolet resonance Raman (UVRR) difference technique describes the structural changes induced by the assembly of the iron cluster and by the reduction of the tyrosyl radical. Spectral contributions from aromatic amino acids are observed through UV resonance enhancement at 229 nm. Vibrational bands are assigned by comparison to histidine, phenylalanine, tyrosine, tryptophan, and 3-methylindole model compound data and by isotopic labeling of histidine in the β2 subunit. Reduction of the tyrosyl radical reveals Y122• Raman bands at 1499 and 1556 cm(-1) and Y122 Raman bands at 1170, 1199, and 1608 cm(-1). There is little perturbation of other aromatic amino acids when Y122• is reduced. Assembly of the iron cluster is shown to be accompanied by deprotonation of histidine. A p(2)H titration study supports the assignment of an elevated pK for the histidine. In addition, structural perturbations of tyrosine and tryptophan are detected. For tryptophan, comparison to model compound data suggests an increase in hydrogen bonding and a change in conformation when the iron cluster is removed. pH and (2)H(2)O studies imply that the perturbed tryptophan is in a low dielectric environment that is close to the metal center and protected from solvent exchange. Tyrosine contributions are attributed to a conformational or hydrogen-bonding change. In summary, our work shows that electrostatic and conformational perturbations of aromatic amino acids are associated with metal cluster assembly in RNR. These conformational changes may contribute to the allosteric effects, which regulate metal binding.


Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice.
We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or fibrosis, while the differential effect of aging on HFD-induced renal injury was not remarkable as shown in the liver.


A Fast and Selective Approach for Profiling Vicinal Diols Using Liquid Chromatography-Post Column Derivatization-Double Precursor Ion Scanning Mass Spectrometry.
Vicinal diols are important signaling metabolites of various inflammatory diseases, and some of them are potential biomarkers for some diseases. Utilizing the rapid reaction between diol and 6-bromo-3-pyridinylboronic acid (BPBA), a selective and sensitive approach was established to profile these vicinal diols using liquid chromatography-post column derivatization coupled with double precursor ion scan-mass spectrometry (LC-PCD-DPIS-MS). After derivatization, all BPBA-vicinal-diol esters gave a pair of characteristic isotope ions resulting from 79Br and 81Br. The unique isotope pattern generated two characteristic fragment ions of m/z 200 and 202. Compared to a traditional offline derivatization technique, the new LC-PCD-DPIS-MS method retained the capacity of LC separation. In addition, it is more sensitive and selective than a full scan MS method. As an application, an in vitro study of the metabolism of epoxy fatty acids by human soluble epoxide hydrolase was tested. These vicinal-diol metabolites of individual regioisomers from different types of polyunsaturated fatty acids were easily identified. The limit of detection (LOD) reached as low as 25 nM. The newly developed LC-PCD-DPIS-MS method shows significant advantages in improving the selectivity and therefore can be employed as a powerful tool for profiling vicinal-diol compounds from biological matrices.


Determinants of smoking cessation among adolescents in South Africa.
Data is required on the motivational determinants of smoking cessation among a multi-ethnic sample of adolescents in South Africa. The I-Change Model was used to explore the determinants of smoking cessation among a sample of 1267 Black African, Colored and White Grade 9-11 monthly smokers and former smokers in the Southern Cape-Karoo region. Across the ethnic groups, former smokers displayed a more positive attitude toward non-smoking, were surrounded by a social environment that was more supportive of non-smoking, displayed higher self-efficacy not to smoke in stressful, routine and social situations, and were more positive about their intention not to smoke in the next year. The I-Change Model can be used to address the cognitions of smoking in a multi-ethnic society like South Africa. However, some ethnic tailoring will be required. Black African students will benefit from a focus on attitudinal cognitions and cultural factors that motivate smoking. Colored students require the involvement of their social environment, while White students will benefit from the development of refusal skills in social situations.


Carotid arterial wall MRI at 3T using 3D variable-flip-angle turbo spin-echo (TSE) with flow-sensitive dephasing (FSD).
To evaluate the effectiveness of flow-sensitive dephasing (FSD) magnetization preparation in improving blood signal suppression of three-dimensional (3D) turbo spin-echo (TSE) sequence (SPACE) for isotropic high-spatial-resolution carotid arterial wall imaging at 3T. The FSD-prepared SPACE sequence (FSD-SPACE) was implemented by adding two identical FSD gradient pulses right before and after the first refocusing 180 degrees -pulse of the SPACE sequence in all three orthogonal directions. Nine healthy volunteers were imaged at 3T with SPACE, FSD-SPACE, and multislice T2-weighted 2D TSE coupled with saturation band (SB-TSE). Apparent carotid wall-lumen contrast-to-noise ratio (aCNR(w-l)) and apparent lumen area (aLA) at the locations with residual-blood (rb) signal shown on SPACE images were compared between SPACE and FSD-SPACE. Carotid aCNR(w-l) and lumen (LA) and wall area (WA) measured from FSD-SPACE were compared to those measured from SB-TSE. Plaque-mimicking flow artifacts identified in seven carotids on SPACE images were eliminated on FSD-SPACE images. The FSD preparation resulted in slightly reduced aCNR(w-l) (P = 0.025), but significantly improved aCNR between the wall and rb regions (P < 0.001) and larger aLA (P < 0.001). Compared to SB-TSE, FSD-SPACE offered comparable aCNR(w-l) with much higher spatial resolution, shorter imaging time, and larger artery coverage. The LA and WA measurements from the two techniques were in good agreement based on intraclasss correlation coefficient (0.988 and 0.949, respectively; P < 0.001) and Bland-Altman analyses. FSD-SPACE is a time-efficient 3D imaging technique for carotid arterial wall with superior spatial resolution and blood signal suppression.


Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools?
This paper explores the issues that arise from the discussion of administering rescue medication to children who experience prolonged convulsive seizures in mainstream schools in the UK. Current guidelines recommend immediate treatment of children with such seizures (defined as seizures lasting more than 5 min) to prevent progression to status epilepticus and neurological morbidity. As children are unconscious during prolonged convulsive seizures, whether or not they receive their treatment in time depends on the presence of a teacher or other member of staff trained and able to administer rescue medication. However, it is thought that the situation varies between schools and depends mainly on the goodwill and resources available locally. A more systematic response is needed to ensure that children receive rescue medication regardless of where their seizure occurs. Possible ways forward include: greater use of training resources for schools available from epilepsy voluntary sector organisations; consistent, practical information to schools; transparent guidance outlining a clear care pathway from the hospital to the school; and implementation and adherence to each child's individual healthcare plan. Children requiring emergency treatment for prolonged convulsive seizures during school hours test the goals of integrated, person-centred care as well as joined-up working to which the National Health Service (NHS) aspires. As changes to the NHS come into play and local services become reconfigured, every effort should be made to take account of the particular needs of this vulnerable group of children within broader efforts to improve the quality of paediatric epilepsy services overall.


[Intratumoral chemotherapy in the treatment of regional widespread pulmonary cancer].
A new method of treatment of pulmonary cancer using the introduction of cytostatic drugs and prednisolone into the tumor during bronchofibroscopy was suggested. This increases the effectiveness of treatment and reduces the side effects of drugs. Complete regression of tumor was observed in 9 (32.1%) patients of the main group, partial regression--in 12 (42.9%). In control group the regression was observed in 6 (20%) and in 10 (33.3%) patients, respectively.


Polyketide proofreading by an acyltransferase-like enzyme.
Trans-acyltransferase polyketide synthases (trans-AT PKSs) are an important group of bacterial enzymes producing bioactive polyketides. One difference from textbook PKSs is the presence of one or more free-standing AT-like enzymes. While one homolog loads the PKS with malonyl units, the function of the second copy (AT2) was unknown. We studied the two ATs PedC and PedD involved in pederin biosynthesis in an uncultivated symbiont. PedD displayed malonyl- but not acetyltransferase activity toward various acyl carrier proteins (ACPs). In contrast, the AT2 PedC efficiently hydrolyzed acyl units bound to N-acetylcysteamine or ACP. It accepted substrates with various chain lengths and functionalizations but did not cleave malonyl-ACP. These data are consistent with the role of PedC in PKS proofreading, suggesting a similar function for other AT2 homologs and providing strategies for polyketide titer improvement and biosynthetic investigations.


Improving problem oriented medical records through self-audit.
In a teaching family medical center a strategy was sought to improve the quality of medical record keeping. A study was undertaken to determine the usefulness of a standardized form for self-audit. Validity and reliability of the form were established and it was shown that there was a significant improvement in the study group three weeks after the exposure period, as compared to a control group. Improvements occurred particularly in the recording of drugs prescribed and in the linkage of progress notes to the problem list. Despite this improvement, linkage to the problem list was seen to occur in only half of the studied charts. With modification the self-audit form appears to be a useful stimulus to good record keeping.


Studies on anemia in F1 hybrid mice injected with parental strain lymphoid cells.
The survival of (51)Cr-labeled erythrocytes has been studied in F(1) hybrid mice in which wasting disease was produced by injection of parental lymphoid cells taken either from lymph nodes and thymus or from the spleen. Coincident with the development of the disease syndrome, there occurred a severe anemia accompanied by a sudden loss of circulating labeled erythrocytes, whether host or parental. This finding suggests that the anemia is not due solely to specific immunologic reaction of donor tissue against host erythrocytes.


The differential development of microsporidia infecting worker honey bee (Apis mellifera) at increasing incubation temperature.
In the last century, nosemosis caused by Nosema apis is traditionally considered as a low-prevalence disease of Apis mellifera, even though it occurs worldwide. Colonies affected by N. apis display low levels of infection during summer, a small peak in autumn and usually a slow rise during winter. However, nosemosis due to Nosema ceranae is considered as an emergent illness that is posing a major threat to the health of individual honey bees and whole bee colonies. The symptoms of infection by these two pathogens are very different, as are the virulence, spread and pathogenicity. We have carried out experiments in artificially infected worker honey bees maintained in the laboratory at two different temperatures. Both microsporidia developed as expected for up to 4 days after infection at 33.0°C, but when maintained for 5 or 7 days at 37.2°C, only N. ceranae completed its life cycle in infected honey bees, while the development of N. apis was inhibited. This and other published data suggest that N. ceranae is eurythermal whereas N. apis is stenothermal. The higher temperature tolerance recorded may be related to the higher prevalence of N. ceranae reported worldwide.


Effects of health screening for adults with intellectual disability: a pooled analysis.
Health screening has been shown to have beneficial effects on health outcomes in adults with intellectual disability. However, the nature of the population, which makes it difficult to recruit, has meant past studies have been relatively small and effect estimates unstable. This study conducted a pooled analysis of two randomised trials and one cohort study, containing a total of 795 participants. Use of a simple, low-cost screening tool produced substantial increases in health-promotion and disease-prevention activity, when compared with usual care.


High intensity interval training for people with multiple sclerosis: A systematic review.
Aerobic high intensity interval training (HIIT) is safe in the general population and more efficient in improving fitness than continuous moderate intensity training. The body of literature examining HIIT in multiple sclerosis (MS) is expanding but to date a systematic review has not been conducted. The aim of this review was to investigate the efficacy and safety of HIIT in people with MS. A systematic search was carried out in September 2017 in EMBASE, MEDline, PEDro, CENTRAL and Web of Science Core collections using appropriate keywords and MeSH descriptors. Reference lists of relevant articles were also searched. Articles were eligible for inclusion if they were published in English, used HIIT, and included participants with MS. Quality was assessed using the PEDro scale. The following data were extracted using a standardised form: study design and characteristics, outcome measures, significant results, drop-outs, and adverse events. Seven studies (described by 11 articles) were identified: four randomised controlled trials, one randomised cross-over trial and two cohort studies. PEDro scores ranged from 3 to 8. Included participants (n = 249) were predominantly mildly disabled; one study included only people with progressive MS. Six studies used cycle ergometry and one used arm ergometry to deliver HIIT. One study reported six adverse events, four which could be attributed to the intervention. The other six reported that there were no adverse events. Six studies reported improvements in at least one outcome measure, however there were 60 different outcome measures in the seven studies. The most commonly measured domain was fitness, which improved in five of the six studies measuring aspects of fitness. The only trial not to report positive results included people with progressive and a more severe level of disability (Extended Disability Status Scale 6.0-8.0). HIIT appears to be safe and effective in increasing fitness in people with MS and low levels of disability. Further research is required to explore the effectiveness of HIIT in people with progressive MS and in those with higher levels of disability.


Mineral composition of Tamarindus indica LINN (tamarind) pulp and seeds from different agro-ecological zones of Uganda.
Mineral composition of dry Tamarindus indica LINN pulp and seeds was evaluated on samples collected from three different agro-ecological zones of Uganda (Lake Victoria Crescent, and Eastern and West Nile). The objective of the study was to evaluate the mineral composition of T. indica pulp and seed samples from across Uganda's different agro-ecological zones and land use types. Separately grounded samples of T. indica pulp and seeds were analyzed for Zn, Fe, Mg, P, Na, K, and Ca. The univariate analysis of variance in the General Linear Model was used to compare differences in mineral composition. Treatment means were separated using Least Significant Difference (LSD) in Post Hoc Tests. The results showed that there were significant differences (p ≤ 0.005) in mineral composition levels of T. indica pulp and seed samples between the different agro-ecological zones with the exception of P and Na (for pulp). The T. indica pulp and seeds samples from the Lake Victoria Crescent zone and wild land use type had generally higher mineral levels than T. indica samples from other agro-ecological zones and different land use types. As mineral composition levels were generally higher in the seed than the pulp samples, consumption of T. indica seeds should be promoted. There is also need to conserve individual species both on-farm and in the wild population, but T. indica mineral concentrations (both pulp and seeds) were higher in the samples from the wild population, making them good for human and animal diets.


Powered Endoscopic Nasal Septal Surgery.
While nasal endoscopy is typically used for diagnosis and sinus surgery, endoscopy can be combined with powered instrumentation to perform nasal septal surgery. Powered Endoscopic Nasal Septum Surgery (PENSS) is an easy, effective and quick alternative to traditional headlight approaches to septoplasty. PENSS limits the dissection to the area of the deviation and markedly reduces the extent of subperichondrial dissection. This is particularly valuable in patients who have undergone prior septal cartilage resection. PENSS was used in 2,730 patients over 8 years. Surgical indications and technique are discussed. These patients had either isolated nasal septal deformities associated with other rhinologic pathology (sinusitis, adenoid hypertrophy polyps and external nasal deformity). PENSS was utilized with video assistance to allow an enhanced view of the endoscopic operative field. These patients were operated upon in an outpatient surgical suite and were seen for a post-operative video endoscopic evaluation at 5, 10, 15 and 20 days after surgery. The patients who had associated functional endoscopic sinus surgery were evaluated as needed until 6 weeks after surgery. There were no delayed complications. Endoscopic resection of septal spurs, deformities and deviations can be performed safely alone or in combination with endoscopic sinus surgery with minimal additional morbidity.


Novel insights into pathological changes in muscular arteries of radiotherapy patients.
Vascular disease is increased after radiotherapy and is an important determinant of late treatment-induced morbidity and excess mortality. This study evaluates the nature of underlying pathologic changes occurring in medium-sized muscular arteries following irradiation. Biopsies of irradiated medium-sized arteries and unirradiated control arteries were taken from 147 patients undergoing reconstructive surgery with a vascularised free flap following treatment for head and neck (H&N) or breast cancer (BC). Relative intimal thickening was derived from the ratio of the thickness of the intima to the thickness of the media (IMR) on histological sections. Proteoglycan, collagen and inflammatory cell content were also scored. Intimal thickness was significantly increased in irradiated vessels: in the H&N group the IMR was 1.5-fold greater without correction for the control artery (p=0.018); in the BC group the IMR increased 1.4-fold after correction for the control artery (p=0.056) at a mean of 4 years following irradiation. There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73% (p=0.024). Inflammatory cell content was increased in the intima of the irradiated H&N vessels (p=0.014). Radiation-induced vascular pathology differs quantitatively and qualitatively from age-related atherosclerosis.


The effect of modelling parameters in the development and validation of knee joint models on ligament mechanics: A systematic review.
The ligaments in the knee are prone to injury especially during dynamic activities. The resulting instability can have a profound impact on a patient's daily activities and functional capacity. Musculoskeletal knee modelling provides a non-invasive tool for investigating ligament force-strain behaviour in various dynamic scenarios, as well as potentially complementing existing pre-planning tools to optimise surgical reconstructions. However, despite the development and validation of many musculoskeletal knee models, the effect of modelling parameters on ligament mechanics has not yet been systematically reviewed. This systematic review aimed to investigate the results of the most recent studies using musculoskeletal modelling techniques to create models of the native knee joint, focusing on ligament mechanics and modelling parameters in various simulated movements. PubMed, ScienceDirect, Google Scholar, and IEEE Xplore. Databases were searched for articles containing any numerical ligament strain or force data on the intact, ACL-deficient, PCL-deficient, or lateral extra-articular reconstructed (LER) knee joints. The studies had to derive these results from musculoskeletal modelling methods. The dates of the publications were between 1 January 1995 and 30 November 2021. A customised data extraction form was created to extract each selected study's critical musculoskeletal model development parameters. Specific parameters of the musculoskeletal knee model development used in each eligible study were independently extracted, including the (1) musculoskeletal model definition (i.e., software used for modelling, knee type, source of geometry, the inclusion of cartilage and menisci, and articulating joints and joint boundary conditions (i.e., number of degrees of freedom (DoF), subjects, type of activity, collected data and type of simulation)), (2) specifically ligaments modelling techniques (i.e., ligament bundles, attachment points, pathway, wrapping surfaces and ligament material properties such as stiffness and reference length), (3) sensitivity analysis, (4) validation approaches, (5) predicted ligament mechanics (i.e., force, length or strain) and (6) clinical applications if available. The eligible papers were then discussed quantitatively and qualitatively with respect to the above parameters. From the 1004 articles retrieved by the initial electronic search, only 25 met all inclusion criteria. The results obtained by aggregating data reported in the eligible studies indicate that considerable variability in the predicted ligament mechanics is caused by differences in geometry, boundary conditions and ligament modelling parameters. This systematic review revealed that there is currently a lack of consensus on knee ligament mechanics. Despite this lack of consensus, some papers highlight the potential of developing translational tools using musculoskeletal modelling. Greater consistency in model design, incorporation of sensitivity assessment of the model outcomes and more rigorous validation methods should lead to better agreement in predictions for ligament mechanics between studies. The resulting confidence in the musculoskeletal model outputs may lead to the development of clinical tools that could be used for patient-specific treatments.


Comparison of prospective risk estimates for postoperative complications: human vs computer model.
Surgical quality improvement tools such as NSQIP are limited in their ability to prospectively affect individual patient care by the retrospective audit and feedback nature of their design. We hypothesized that statistical models using patient preoperative characteristics could prospectively provide risk estimates of postoperative adverse events comparable to risk estimates provided by experienced surgeons, and could be useful for stratifying preoperative assessment of patient risk. This was a prospective observational cohort. Using previously developed models for 30-day postoperative mortality, overall morbidity, cardiac, thromboembolic, pulmonary, renal, and surgical site infection (SSI) complications, model and surgeon estimates of risk were compared with each other and with actual 30-day outcomes. The study cohort included 1,791 general surgery patients operated on between June 2010 and January 2012. Observed outcomes were mortality (0.2%), overall morbidity (8.2%), and pulmonary (1.3%), cardiac (0.3%), thromboembolism (0.2%), renal (0.4%), and SSI (3.8%) complications. Model and surgeon risk estimates showed significant correlation (p < 0.0001) for each outcome category. When surgeons perceived patient risk for overall morbidity to be low, the model-predicted risk and observed morbidity rates were 2.8% and 4.1%, respectively, compared with 10% and 18% in perceived high risk patients. Patients in the highest quartile of model-predicted risk accounted for 75% of observed mortality and 52% of morbidity. Across a broad range of general surgical operations, we confirmed that the model risk estimates are in fairly good agreement with risk estimates of experienced surgeons. Using these models prospectively can identify patients at high risk for morbidity and mortality, who could then be targeted for intervention to reduce postoperative complications.


[Out-of-Hospital Cardiopulmonary Resuscitation].
With an incidence of 50 - 70 resuscitations attempted per 100000 inhabitants and year Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death in adults in the developed world. Thus, cardiac arrest is a common emergency situation attended by emergency medical services (EMS). Due to the pathophysiology it is one of the most time-critical emergencies: after 3 - 5 minutes of cardiac arrest without resuscitation efforts the likelihood of neurological impairments is significantly increased once the patient survives the initial event. Therefore, the immediate start of basic life support (BLS) with high quality chest compressions is paramount. Advanced life support comprises defibrillation, if indicated, airway management, the application of selected drugs and the treatment of reversible causes. After return of spontaneous circulation (ROSC) a structured post-resuscitation care in EMS and in dedicated hospitals is essential to achieve the best neurological outcome for the patient. The universal resuscitation algorithm has to be adapted for special circumstances of OHCA (e. g. a traumatic cause, cardiac arrest in pregnancy, …).


Elution of exocellular enzymes from Saccharomyces fragilis and Saccharomyces cerevisiae.
Weimberg, Ralph (Northern Regional Research Laboratory, Peoria, Ill.), and William L. Orton. Elution of exocellular enzymes from Saccharomyces fragilis and Saccharomyces cerevisiae. J. Bacteriol. 91:1-13. 1966.-Invertase and acid phosphatase are repressible exocellular enzymes in Saccharomyces fragilis and S. cerevisiae. The conditions for eluting these enzymes from both organisms were compared. Either KCl or beta-mercaptoethanol eluted the enzymes from S. fragilis, and the amounts eluted varied quantitatively according to the physiological age of the organism. In addition to eluting enzymatic activity from the cells, these reagents also caused a large increase in the amount of activity that remained associated with the cells of S. fragilis. Invertase and acid phosphatase were not removed from cells of S. cerevisiae by KCl or beta-mercaptoethanol. These enzymes were separated from S. cerevisiae cells only when there was some degree of cell-wall digestion by snail gut fluid.


Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells.
Endothelial insulin resistance represents a causal factor in the pathogenesis of type 2 diabetes (T2D) and vascular disease, thus the need to identify molecular mechanisms underlying defects in endothelial insulin signaling. We previously have shown that a disintegrin and metalloproteinase-17 (ADAM17) is increased while insulin receptor α-subunit (IRα) is decreased in the vasculature of patients with T2D, leading to impaired insulin-induced vasodilation. We have also demonstrated that ADAM17 sheddase activity targets IRα; however, the mechanisms driving endothelial ADAM17 activity in T2D are largely unknown. Herein, we report that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane causes ADAM17-mediated shedding of IRα and blunting of insulin signaling in endothelial cells. Furthermore, we demonstrate that endothelial PS externalization is mediated by the phospholipid scramblase anoctamin-6 (ANO6) and that this process can be stimulated by neuraminidase, a soluble enzyme that cleaves sialic acid residues. Of note, we demonstrate that men and women with T2D display increased levels of neuraminidase activity in plasma, relative to age-matched healthy individuals, and this occurs in conjunction with increased ADAM17 activity and impaired leg blood flow responses to endogenous insulin. Collectively, this work reveals the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.


The default mode network: where the idiosyncratic self meets the shared social world.
The default mode network (DMN) is classically considered an 'intrinsic' system, specializing in internally oriented cognitive processes such as daydreaming, reminiscing and future planning. In this Perspective, we suggest that the DMN is an active and dynamic 'sense-making' network that integrates incoming extrinsic information with prior intrinsic information to form rich, context-dependent models of situations as they unfold over time. We review studies that relied on naturalistic stimuli, such as stories and movies, to demonstrate how an individual's DMN neural responses are influenced both by external information accumulated as events unfold over time and by the individual's idiosyncratic past memories and knowledge. The integration of extrinsic and intrinsic information over long timescales provides a space for negotiating a shared neural code, which is necessary for establishing shared meaning, shared communication tools, shared narratives and, above all, shared communities and social networks.


Hierarchical interactions model for predicting Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD) conversion.
Identifying patients with Mild Cognitive Impairment (MCI) who are likely to convert to dementia has recently attracted increasing attention in Alzheimer's disease (AD) research. An accurate prediction of conversion from MCI to AD can aid clinicians to initiate treatments at early stage and monitor their effectiveness. However, existing prediction systems based on the original biosignatures are not satisfactory. In this paper, we propose to fit the prediction models using pairwise biosignature interactions, thus capturing higher-order relationship among biosignatures. Specifically, we employ hierarchical constraints and sparsity regularization to prune the high-dimensional input features. Based on the significant biosignatures and underlying interactions identified, we build classifiers to predict the conversion probability based on the selected features. We further analyze the underlying interaction effects of different biosignatures based on the so-called stable expectation scores. We have used 293 MCI subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) database that have MRI measurements at the baseline to evaluate the effectiveness of the proposed method. Our proposed method achieves better classification performance than state-of-the-art methods. Moreover, we discover several significant interactions predictive of MCI-to-AD conversion. These results shed light on improving the prediction performance using interaction features.


Endovascular Aneurysm Sealing is Associated with Higher Medium-Term Survival than Traditional EVAR.
Endovascular aneurysm repair (EVAR) is the dominant treatment modality for abdominal aortic aneurysm (AAA). Periprocedural risks are low, and cardiovascular events are the principle determinants of long-term survival. Recently, the concept of endovascular aneurysm sealing (EVAS) has been introduced into clinical investigation. In previous cohort studies, EVAS has been associated with a lower all-cause mortality than expected despite device issues. We used a propensity weighted approach to investigate whether EVAS was associated with lower all-cause mortality after aneurysm repair. We compared 333 patients in the Nellix United States Investigational Device Exemption trial to 15,431 controls from the Vascular Quality Initiative between 2014 and 2016 after applying the exclusion criteria from the investigational device exemption (hemodialysis, creatinine > 2.0 mg/dL, or rupture). We calculated propensity scores and applied inverse probability weighting to compare risk adjusted medium-term survival using Kaplan-Meier and Cox regression. After weighting, patients treated with the Nellix EVAS system experienced higher 3-year survival than controls from the Vascular Quality Initiative (93% vs. 88%, respectively). This corresponded to a 41% lower risk of mortality for EVAS compared with EVAR (HR 0.59 [0.38-0.92], P = 0.02). Subgroup analysis demonstrated that the association between EVAS and higher survival was strongest in the subgroup of patients with aneurysms over 5.5 cm (P for interaction < 0.001). In this subgroup, EVAS patients experienced half the rate of mortality as those patients treated with EVAR, with 3-year survival of 92% compared with 86% (HR 0.5 [0.3-0.9], P = 0.02). In this select group of patients, EVAS was associated with higher medium-term survival than traditional EVAR. Although issues with the device have recently surfaced, this exploratory analysis shows that the concept of sac sealing may hold promise. Further study is needed to confirm this finding and determine whether EVAS is associated with lower rates of cardiovascular events.


Temporal dynamics of cortical sources underlying spontaneous and peripherally evoked slow waves.
Slow waves are the most prominent electroencephalographic feature of non-rapid eye movement (NREM) sleep. During NREM sleep, cortical neurons oscillate approximately once every second between a depolarized upstate, when cortical neurons are actively firing, and a hyperpolarized downstate, when cortical neurons are virtually silent (Destexhe et al., 1999; Steriade et al., 1993a, 2001). Intracellular recordings indicate that the origins of the slow oscillation are cortical and that corticocortical connections are necessary for their synchronization (Amzica and Steriade, 1995; Steriade et al., 1993b; Timofeev and Steriade, 1996; Timofeev et al., 2000). The currents produced by the near-synchronous slow oscillation of large populations of neurons appear on the scalp as electroencephalogram (EEG) slow waves (Amzica and Steriade, 1997). Despite this cellular understanding, questions remain about the role of specific cortical structures in individual slow waves. Early EEG studies of slow waves in humans were limited by the small number of derivations employed and by the difficulty of relating scalp potentials to underlying brain activity (Brazier, 1949; Roth et al., 1956). Functional neuroimaging methods offer exceptional spatial resolution, but lack the temporal resolution to track individual slow waves (Dang-Vu et al., 2008; Maquet, 2000). Intracranial recordings in patient populations are limited by the availability of medically necessary electrode placements and can be confounded by pathology and medications (Cash et al., 2009; Nir et al., 2011; Wenneberg 2010). Source modeling of high-density EEG recordings offers a unique opportunity for neuroimaging sleep slow waves. So far, the results have challenged several of the influential topographic observations about slow waves that had persisted since the original EEG recordings of sleep. These recent analyses revealed that individual slow waves are idiosyncratic cortical events and that the negative peak of the EEG slow wave often involves cortical structures not necessarily apparent from the scalp, like the inferior frontal gyrus, anterior cingulate, posterior cingulate, and precuneus (Murphy et al., 2009). In addition, not only do slow waves travel (Massimini et al., 2004), but they often do so preferentially through the areas comprising the major connectional backbone of the human cortex (Hagmann et al., 2008). In this chapter, we will review the cellular, intracranial recording, and neuroimaging results concerning EEG slow waves. We will also confront a long held belief about peripherally evoked slow waves, also known as K-complexes, namely that they are modality independent and do not involve cortical sensory pathways. The analysis included here is the first to directly compare K-complexes evoked with three different stimulation modalities within the same subject on the same night using high-density EEG.


Rapid perceptual learning of noise-vocoded speech requires attention.
Humans are able to adapt to unfamiliar forms of speech (such as accented, time-compressed, or noise-vocoded speech) quite rapidly. Can such perceptual learning occur when attention is directed away from the speech signal? Here, participants were simultaneously exposed to noise-vocoded sentences, auditory distractors, and visual distractors. One group attended to the speech, listening to each sentence and reporting what they heard. Two other groups attended to either the auditory or visual distractors, performing a target-detection task. Only the attend-speech group benefited from the exposure when subsequently reporting noise-vocoded sentences. Thus, attention to noise-vocoded speech appears necessary for learning.